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Association of p53 codon 72 polymorphism with susceptibility to hepatocellular carcinoma in a Chinese population from northeast Sichuan.

ABSTRACT: The p53 tumor suppressor gene is key in tumor development and progression, and the single nucleotide polymorphism (SNP) of the p53 gene codon 72 (p53Arg/Pro) changes the structure of the protein. In addition, it affects its activity, which may affect cancer risk. The aim of the present study was to investigate the association between p53 codon 72 polymorphism and susceptibility to hepatocellular carcinoma (HCC) in a Chinese population from northeast Sichuan. A total of 342 HCC patients and 347 non-cancer control subjects were recruited, and the polymorphism of p53 codon 72 was measured by TaqMan^® minor groove binder fluorescent quantitative polymerase chain reaction assay. The distribution frequency of p53 sites of arginine (Arg)/Arg, Arg/proline (Pro), Pro/Pro were 18.4, 48.8 and 32.8% in the control group, as compared with 18.7, 49.9 and 31.4% in the case group, which indicated that there was no difference between two groups (?²=0.14; P=0.93). Upon further stratification with smoking, alcohol consumption, gender and hepatitis B virus (HBV) infection, no risk increasing genotype was identified. However, interactions between p53 codon 72 SNP and smoking, alcohol consumption and HBV infection may increase the risk of HCC [smoking odds ratio (OR), 2.00; 95% confidence interval (CI), 1.21-3.29; alcohol consumption OR, 1.87; 95% CI, 1.08-3.26; HBV infection OR, 1.84; 95% CI, 1.10-3.08]. No significant association was identified between p53 codon 72 polymorphism and HCC, and it may not have an independent effect on the susceptibility to HCC in a Chinese population from northeast Sichuan. However, interaction between genetic factors and environment exposure significantly increased the risk of HCC.

SUBMITTER: Cai J

PROVIDER: S-EPMC5351203 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Association of p53 codon 72 polymorphism with susceptibility to hepatocellular carcinoma in a Chinese population from northeast Sichuan.

Cai Jiajing J Cai Yan Y Ma Qiang Q Chang Fan F Xu Lei L Zhang Guoyuan G Guo Xiaolan X

Biomedical reports 20170111 2

The p53 tumor suppressor gene is key in tumor development and progression, and the single nucleotide polymorphism (SNP) of the p53 gene codon 72 (p53Arg/Pro) changes the structure of the protein. In addition, it affects its activity, which may affect cancer risk. The aim of the present study was to investigate the association between p53 codon 72 polymorphism and susceptibility to hepatocellular carcinoma (HCC) in a Chinese population from northeast Sichuan. A total of 342 HCC patients and 347 n ...[more]

PMID: 28357076

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Project description:Squamous cell carcinoma of the penis is a rare but often aggressive disease. A large proportion of penile cancers are associated with HPV infection, mainly with HPV high-risk subtypes 16 and 18. From other HPV-related malignancies a link between a functional SNP in the p53 gene (rs1042522, p.Arg72Pro) and a higher disease risk in the presence of HPV is documented. The p53 p.Arg72 variant was described as a risk factor for developing a malignancy in combination with the presence of HPV as the p.72Arg variant is more prone to HPV E6 protein-mediated degradation than the p.72Pro variant. For penile carcinoma there are only sparse data available on this topic. We therefore analyzed the distribution of this p53 codon 72 SNP in a cohort of 107 penile cancer patients and a healthy control group (n=194) using Restriction Fragment Length Polymorphism (RFLP) analysis. After DNA isolation a PCR amplicon including the variant nucleotide was generated. Based on the variant nucleotide this amplicon can be cleaved into two parts or remain unaffected by a restriction enzyme. Subsequent electrophoresis allowed the discrimination of SNP alleles in the investigated sample. Comparison of the allelic variants revealed no significant differences in the distribution of this SNP between cases and controls (p=0,622). There was also no difference in SNP distribution between cases with/without HPV infection (p=0,558) or histologic variants (p=0.339). In order to strengthen the impact of our data we performed a combined analysis of all published data on this topic with our results. This ended up in SNP distribution data from 177 cases and 1149 controls. Overall, there were also no significant differences in the allelic distribution of the p53 codon 72 SNP between either cases and controls (p=0,914) or HPV-positive and HPV-negative cases (p=0,486). From this most comprehensive data available to date we conclude that there is no influence of the p53 codon 72 SNP on the risk of development of penile carcinoma in Caucasians even in the presence of HPV.

Project description:INTRODUCTION: The absence of mutation or promoter hypermethylation in the BRCA2 gene in the majority of breast cancer cases has indicated alternative ways of its involvement, deregulated expression being one possibility. We show how a polymorphism in the 5' untranslated region (UTR) of BRCA2 can serve as one such factor. Based on the hypothesis that variants of genes involved in the same pathway can influence the risk provided for breast cancer, the status of p53 codon 72 polymorphism was also investigated and a possible interaction between the polymorphisms was examined. METHODS: The luciferase reporter assay followed by RNA secondary structure analysis was used for the functional characterization of -26 5' UTR G>A polymorphism in BRCA2. The genotype and the allele frequency for the polymorphisms were determined and relative risk adjusted for age was calculated in a case-control study of 576 individuals (243 patients and 333 controls) from north India. RESULTS: -26 G>A polymorphism in the 5' UTR of BRCA2 was found to be functional whereby the A allele increased the reporter gene expression by twice that of the G allele in MCF-7 (P = 0.003) and HeLa (P = 0.013) cells. RNA secondary structure analysis by two different programs predicted the A allele to alter the stability of a loop in the vicinity of the translation start site. Its direct implication in breast cancer became evident by a case-control study in which the heterozygous genotype was found to be protective in nature (P heterozygote advantage model = 0.0005, odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.4 to 0.8), which was further supported by trends observed in a genomic instability study. The p53 codon 72 Arg homozygous genotype was found to be over-represented in patients (P = 0.0005, OR = 2.3, 95% CI = 1.4 to 3.6). The interaction study indicated an increased protection under simultaneous presence of protector genotypes of both the polymorphic loci (P = 0.0001, OR = 0.2, 95% CI = 0.1 to 0.4). CONCLUSION: Our study shows that -26 5' UTR polymorphism in BRCA2 can modulate the fine-tuned regulation of the multifunctional gene BRCA2 and renders risk or protection according to the genotype status in the sporadic form of breast cancer, which is further influenced by the germline genetic backgrounds of codon 72 polymorphism of p53.

Project description:BACKGROUND: PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines. Loss of Shp2 promotes hepatocellular carcinoma (HCC), suggesting that PTPN11 functions as a tumor suppressor in HCC tumorgenesis. The aim of this study was to evaluate the effects of the short tandem repeat (STR) polymorphism (rs199618935) within 3'UTR of PTPN11 on HCC susceptibility in Chinese populations. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the associations in 400 patients from Jiangsu province of China, validating the findings in an additional 305 patients from Shanghai of China. Unconditional logistic regression was used to analyze the association between rs199618935 and HCC risk. Additional biochemical investigations and in-silico studies were used to evaluate the possible functional significance of this polymorphism. Logistic regression analysis showed that compared with individuals carrying shorter alleles (11 and 12 repeats), those subjects who carry longer alleles (13 and 14 repeats) had a significantly decreased risk of HCC [adjusted odds ratio (OR) = 0.63, 95% confidence interval (CI) ?= 0.53-0.76, P = 2.00 × 10(-7)], with the risk decreased even further in those carrying allele 15 and 16 (adjusted OR = 0.46, 95% CI = 0.34-0.62, P = 1.00 × 10(-7)). Biochemical investigations showed that longer alleles of rs199618935 conferred higher PTPN11 expression in vivo and in vitro. The altered luciferase activities in reporter gene system suggested that STR regulation of PTPN11 expression could be a transcriptional event. Finally, in-silico prediction revealed that different alleles of rs199618935 could alter the local structure of PTPN11 mRNA. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings suggested that the STR polymorphism within PTPN11 contributes to hepatocarcinogenesis, possibly by affecting PTPN11 expression through a structure-dependent mechanism. The replication of our studies and further functional studies are needed to validate our findings.

Dataset Information

Association of p53 codon 72 polymorphism with susceptibility to hepatocellular carcinoma in a Chinese population from northeast Sichuan.

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Association of p53 codon 72 polymorphism with susceptibility to hepatocellular carcinoma in a Chinese population from northeast Sichuan.

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